Over 100,000 Americans of all ages suffer from inherited retinal diseases (IRD), which cause a progressive loss of vision. In most IRDs, disease begins in the rods, causing vision loss from the periphery to the center, leaving patients unable to navigate their surroundings. Electronic retinal prosthesis restore useful vision in patients affected by IRDs, and optogenetics is an alternative therapeutic. A major limitation of microbial opsins for restoration of retinal light sensitivity is the high light intensity required for activating channelrhodopsins. A solution to this caveat is the use of opsins with higher light sensitivity but sufficiently fast kinetics for useful motion vision. We propose a novel approach to restore vision to patients using a virus to express a light sensitive protein in specific, second-order retina neurons to make them light sensitive. Our approach uses a common neuronal receptor, modified to add a light receptive function to the remaining light-insensitive retinal neurons that survive after photoreceptor degeneration. The receptor uses either retinal, which is available in the eye, or a synthetic chemical photoswitch delivered by intravitreal injection. In this way, the cells in which the receptor is located respond to light with a change in neural firing. This compensates for their loss of input from photoreceptors, restoring light responsiveness to the retina and sending information to the brain to restore vision. In most cases, this approach is independent of the mutation that caused the photoreceptor degeneration. Exceptions to this approach may be diseases that cause RPE cell death, such as choroideremia. To date, versions of this approach, developed by Co-PIs Isacoff and Flannery, and others in the field, have employed receptors that are rather insensitive to light or very slow in response and so could not support normal vision. We now propose a new strategy that uses the natural amplification properties of GPCR signaling to increase sensitivity (by 1000 times) and speed. GPCR signaling cascades are intrinsic to rods and cones, as well as bipolar, ganglion cells and other cells in the retina. We also pursue a new discovery, emerging from our preliminary experiments, which enables a combinatorial approach that uses more than one optical sensor molecule at a time in order to recreate the natural diversity of natural signaling in the retina that had earlier been missing. Finally, we employ sophisticated behavioral analysis to test not only the restoration of the ability to tell light from dark or flashing from steady light, but to determine if the animal is able to see images. Success of this program would represent a major step in the creation of a retinal prosthetic based on gene therapy.